OVERALL ? PROJECT SUMMARY Khosla/Kirkland This Program Project Grant (PPG) application reflects the merging of 2 PPGs at the Mayo Clinic Robert and Arlene Kogod Center on Aging: P01 AG041122 (?Cellular Senescence and Aging,? James Kirkland, PI) and P01 AG004875 (?Physiology of Bone Metabolism in an Aging Population,? Sundeep Khosla, PI). Over the past five years, these two research programs have become increasingly aligned. Thus, rather than submitting separate PPG renewal applications, Drs. Kirkland and Khosla are joining forces as Co-Principal Investigators in this multi-site application in order to maximize synergies and optimize costs to NIA. There is now overwhelming evidence that the accumulation of DNA damage and/or other cellular stressors cause cells to undergo senescence, characterized by profound chromatin changes. Senescent cells can also develop a senescence-associated secretory phenotype (SASP), comprising pro-inflammatory cytokines, chemokines, and extracellular matrix-degrading proteins that have deleterious paracrine and systemic effects. Importantly, key observations made by the investigators in this application have established that reducing the burden of senescent cells in chronologically-aged mice extended healthspan and improved measures of metabolic dysfunction, skeletal fragility, vascular dysfunction, and muscle dysfunction/frailty ? conditions that lie at the nexus of the majority of aging co-morbidities. Thus, the overall goal of this multi-disciplinary, multi- site PPG application is to build a firm foundation of discovery science in cellular senescence that leads to a pipeline of therapeutic strategies that will slow or prevent age-associated diseases. We have assembled an investigative team with expertise in evaluating the effects of clearing senescent cells on multiple organ systems; performing detailed histopathological, molecular, and cellular analyses on the effects of genetic or pharmacological clearance of senescent cells; and developing novel therapeutic strategies to alter senescent cell function or burden. We will leverage shared innovative genetic models and cutting-edge investigational technologies to dissect the tissue- and disease-specific roles of senescent cells in health and disease. The four projects in this PPG focus on the role of cellular senescence in mediating age-related Metabolic Dysfunction (Project 1), Skeletal Fragility (Project 2), Vascular Dysfunction (Project 3), and Skeletal Muscle Loss and Dysfunction (Project 4). These projects will be anchored by 4 cores: Administrative and Biostatistics Core (Core A); Drug Discovery and Development Core (Core B); Integrated Healthspan Phenotyping Core (Core C); and Geroscience Pathology and Cellular Histology Core (Core D). This highly integrated PPG will use a number of common tools and approaches, further underscoring the need for a PPG rather than individual R01 grants. Collectively, the proposed studies will test the Geroscience Hypothesis that targeting a fundamental aging mechanism, cellular senescence, will delay, prevent, or alleviate multiple age-related disorders.